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Oxidative stress (OS) is hypothesized to be a key physiological mechanism mediating life-history trade-offs, but evidence from wild populations experiencing natural environmental variation is limited. We tested the hypotheses that increased early life growth rate increases OS, and that increased OS reduces first-winter survival, in wild Soay sheep (Ovis aries) lambs. We measured growth rate and first-winter survival for four consecutive cohorts, and measured two markers of oxidative damage (malondialdehyde (MDA), protein carbonyls (PC)) and two markers of antioxidant (AOX) protection (total AOX capacity (TAC), superoxide dismutase (SOD)) from blood samples. Faster lamb growth was weakly associated with increased MDA, but not associated with variation in the other three markers. Lambs with higher SOD activity were more likely to survive their first winter, as were male but not female lambs with lower PC concentrations. Survival did not vary with MDA or total TAC. Key predictions relating OS to growth and survival were therefore supported in some OS markers, but not others. This suggests that different markers capture different aspects of the complex relationships between individual oxidative state, physiology and fitness, and that overarching hypotheses relating OS to life-history variation cannot be supported or refuted by studying individual markers., (© 2016 The Authors.)

While oxidative damage owing to reactive oxygen species (ROS) often increases with advancing age and is associated with many age-related diseases, its causative role in ageing is controversial. In particular, studies that have attempted to modulate ROS-induced damage, either upwards or downwards, using antioxidant or genetic approaches, generally do not show a predictable effect on lifespan. Here, we investigated whether dietary supplementation with either vitamin E (α-tocopherol) or vitamin C (ascorbic acid) affected oxidative damage and lifespan in short-tailed field voles, Microtus agrestis. We predicted that antioxidant supplementation would reduce ROS-induced oxidative damage and increase lifespan relative to unsupplemented controls. Antioxidant supplementation for nine months reduced hepatic lipid peroxidation, but DNA oxidative damage to hepatocytes and lymphocytes was unaffected. Surprisingly, antioxidant supplementation significantly shortened lifespan in voles maintained under both cold (7 ± 2°C) and warm (22 ± 2°C) conditions. These data further question the predictions of free-radical theory of ageing and critically, given our previous research in mice, indicate that similar levels of antioxidants can induce widely different interspecific effects on lifespan.

Insulin receptor substrate-1 null (Irs1 (-/-)) mice are long lived and importantly they also demonstrate increased resistance to several age-related pathologies compared to wild type (WT) controls. Currently, the molecular mechanisms that underlie lifespan extension in long-lived mice are unclear although protection against oxidative damage may be important. Here, we determined both the activities of several intracellular antioxidants and levels of oxidative damage in brain, skeletal muscle, and liver of Irs1 (-/-) and WT mice at 80, 450, and 700 days of age, predicting that long-lived Irs1 (-/-) mice would be protected against oxidative damage. We measured activities of both intracellular superoxide dismutases (SOD); cytosolic (CuZnSOD) and mitochondrial (MnSOD), glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT), and reduced glutathione (GHS). Of these, only hepatic CAT was significantly altered (increased) in Irs1 (-/-) mice. In addition, the levels of protein oxidation (protein carbonyl content) and lipid peroxidation (4-hydroxynonenal) were unaltered in Irs1 (-/-) mice, although the hepatic GSH/GSSG ratio, indicating an oxidized environment, was significantly lower in long-lived Irs1 (-/-) mice. Overall, our results do not support the premise that lifespan extension in Irs1 (-/-) mice is associated with greater tissue antioxidant protection or reduced oxidative damage.

A central principle in life-history theory is that reproductive effort negatively affects survival. Costs of reproduction are thought to be physiologically based, but the underlying mechanisms remain poorly understood. Using female North American red squirrels (Tamiasciurus hudsonicus), we test the hypothesis that energetic investment in reproduction overwhelms investment in antioxidant protection, leading to oxidative damage. In support of this hypothesis we found that the highest levels of plasma protein oxidative damage in squirrels occurred during the energetically demanding period of lactation. Moreover, plasma protein oxidative damage was also elevated in squirrels that expended the most energy and had the lowest antioxidant protection. Finally, we found that squirrels that were food-supplemented during lactation and winter had increased antioxidant protection and reduced plasma protein oxidative damage providing the first experimental evidence in the wild that access to abundant resources can reduce this physiological cost., (© 2012 The Author(s). Evolution © 2012 The Society for the Study of Evolution.)

The Free Radical Theory of Ageing (FRTA) predicts that oxidative stress, induced when levels of reactive oxygen species exceed the capacity of antioxidant defenses, causes ageing. Recently, it has also been argued that oxidative damage may mediate important life-history trade-offs. Here, we use inbred lines of the decorated cricket, Gryllodes sigillatus, to estimate the genetic (co)variance between age-dependent reproductive effort, life span, ageing, oxidative damage, and total antioxidant capacity within and between the sexes. The FRTA predicts that oxidative damage should accumulate with age and negatively correlate with life span. We find that protein oxidation is greater in the shorter lived sex (females) and negatively genetically correlated with life span in both sexes. However, oxidative damage did not accumulate with age in either sex. Previously we have shown antagonistic pleiotropy between the genes for early-life reproductive effort and ageing rate in both sexes, although this was stronger in females. In females, we find that elevated fecundity early in life is associated with greater protein oxidation later in life, which is in turn positively correlated with the rate of ageing. Our results provide mixed support for the FRTA but suggest that oxidative stress may mediate sex-specific life-history strategies in G. sigillatus., (© 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.)

The idea that resources are limited and animals can maximise fitness by trading costly activities off against one another forms the basis of life-history theory. Although investment in reproduction or growth negatively affects survival, the mechanisms underlying such trade-offs remain obscure. One plausible mechanism is oxidative damage to proteins, lipids, and nucleic acids caused by reactive oxygen species (ROS). Here, we critically evaluate the premise that ROS-induced oxidative damage shapes life history, focussing on birds and mammals, and highlight the importance of ecological studies examining free-living animals within this experimental framework. We conclude by emphasising the value of using multiple assays to determine oxidative protection and damage. We also highlight the importance of using standardised and appropriate protocols, and discuss future research directions., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Recent work on a small European cave salamander (Proteus anguinus) has revealed that it has exceptional longevity, yet it appears to have unexceptional defences against oxidative damage. This paper comes at the end of a string of other studies that are calling into question the free-radical damage theory of ageing. This theory rose to prominence in the 1990s as the dominant theory for why we age and die. Despite substantial correlative evidence to support it, studies in the last five years have raised doubts over its importance. In particular, these include studies of mice with the major antioxidant genes knocked out (both singly and in combination), which show the expected elevation in oxidative damage but no impact on lifespan. Combined, these findings raise fundamental questions over whether the free-radical damage theory remains useful for understanding the ageing process, and variation in lifespan and life histories., (Copyright © 2011 WILEY Periodicals, Inc.)

Life-history theory assumes that animal life histories are a consequence of trade-offs between current activities and future reproductive performance or survival, because resource supply is limited. Empirical evidence for such trade-offs in the wild are common, yet investigations of the underlying mechanisms are rare. Life-history trade-offs may have both physiological and ecological mediated costs. One hypothesized physiological mechanism is that elevated energy metabolism may increase reactive oxygen species production, leading to somatic damage and thus compromising future survival. We investigated the impact of experimentally elevated energy expenditure on oxidative damage, protection and lifespan in short-tailed field voles (Microtus agrestis) maintained in captivity to remove any confounding ecological factor effects. Energy expenditure was elevated via lifelong cold exposure (7+/-2 degrees C), relative to siblings in the warm (22+/-2 degrees C). No treatment effect on cumulative mortality risk was observed, with negligible effects on oxidative stress and antioxidant protection. These data suggest that in captive animals physiologically mediated costs on life history do not result from increased energy expenditure and consequent elevations in oxidative stress and reduced survival.

The effects of dietary antioxidant supplementation on oxidative stress and life span are confused. We maintained C57BL/6 mice at 7 +/- 2 degrees C and supplemented their diet with alpha-tocopherol from 4 months of age. Supplementation significantly increased (p = 0.042) median life span by 15% (785 days, n = 44) relative to unsupplemented controls (682 days, n = 43) and also increased maximum life span (oldest 10%, p = 0.028). No sex or sex by treatment interaction effects were observed on life span, with treatment having no effect on resting or daily metabolic rate. Lymphocyte and hepatocyte oxidative DNA damage and hepatic lipid peroxidation were unaffected by supplementation, but hepatic oxidative DNA damage increased with age. Using a cDNA macroarray, genes associated with xenobiotic metabolism were significantly upregulated in the livers of female mice at 6 months of age (2 months supplementation). At 22 months of age (18 months supplementation) this response had largely abated, but various genes linked to the p21 signaling pathway were upregulated at this time. We suggest that alpha-tocopherol may initially be metabolized as a xenobiotic, potentially explaining why previous studies observe a life span extension generally when lifelong supplementation is initiated early in life. The absence of any significant effect on oxidative damage suggests that the life span extension observed was not mediated via any antioxidant properties of alpha-tocopherol. We propose that the life span extension observed following alpha-tocopherol supplementation may be mediated via upregulation of cytochrome p450 genes after 2 months of supplementation and/or upregulation of p21 signaling genes after 18 months of supplementation. However, these signaling pathways now require further investigation to establish their exact role in life span extension following alpha-tocopherol supplementation.

Oxidative metabolism has reactive oxygen species (ROS) as unavoidable by-products, and the damage ROS inflicts on DNA, proteins and lipids is considered to be a major agent of senescence. Increasing reproductive effort accelerates senescence, but whether reproductive effort is increased at the expense of protection against oxidative damage has not yet been tested. We manipulated reproductive effort in zebra finches through brood size manipulation and measured the activity of two major antioxidant enzymes (superoxide dismutase (SOD) and glutathione peroxidase (GPx)) in the pectoral muscle after 19-20 days of brood rearing. Oxidative stress is reflected by the balance between oxidative protection and ROS exposure, and we therefore scaled SOD and GPx activity to daily energy expenditure (DEE) as an index of ROS production. SOD and GPx activity decreased with increasing brood size by 28% and 24%, respectively. This effect was identical in the two sexes, but arose in different ways: males did not change their DEE, but had lower absolute enzyme activity, and females increased their DEE, but did not change absolute enzyme activity. This result suggests that senescence acceleration by increased reproductive effort is at least in part mediated by oxidative stress.

Calcium deficiency is considered to increase intracellular calcium level; thus the aim of the current study was to elucidate whether dietary calcium restriction enhanced exercise-induced oxidative stress in rat diaphragm. Twenty male Wistar rats were randomly assigned to either a control group or a group subjected to 1 mo of calcium restriction. In addition, each group was subsequently subdivided into rested or acutely exercised group. Dietary calcium restriction significantly (P < 0.05) upregulated the activities of manganese-superoxide dismutase (Mn-SOD), copper-zinc-superoxide dismutase (Cu-Zn-SOD), and glutathione peroxidase (Gpx) but not catalase. Acute exercise, in addition to calcium restriction, decreased both SOD isoenzymes in the diaphragm of calcium-restricted rats (P < 0.05). On the other hand, calcium restriction resulted in increased Gpx mRNA expression (P < 0.05). In control rats, acute exercise significantly (P < 0.05) increased the expressions of both SOD mRNAs, whereas in the calcium-restricted rats, it increased that of Mn-SOD mRNA (P < 0.05) but decreased that of Gpx mRNA (P < 0.05). Furthermore, reactive carbonyl derivative, a marker of protein oxidation, was significantly greater in the calcium-restricted rats than in the control rats after acute exercise (P < 0.05). The results suggest that antioxidant enzymes in rat diaphragm were upregulated in response to an increased oxidative stress by dietary calcium restriction but that upregulation is not enough to cope with exercise-induced further increase of oxidative stress.